DIFICLIR 200mg tablets medication leaflet

DIFICLIR 200 mg film-coated tablets

Each film-coated tablet contains 200 mg of fidaxomicin.

For the full list of excipients, see section 6.1.

Film-coated tablet.

Capsule shaped tablets of 14 mm, white to off-white in colour, debossed with “FDX” on one side and“200” on the other side.

DIFICLIR film-coated tablets is indicated for the treatment of Clostridioides difficile infections (CDI)also known as C. difficile-associated diarrhoea (CDAD) in adult and paediatric patients with a bodyweight of at least 12.5 kg (see section 4.2 and 5.1).

Consideration should be given to official guidelines on the appropriate use of antibacterial agents.

Standard dosing

The recommended dose is 200 mg (one tablet) administered twice daily (once every 12 hours) for10 days (see section 5.1).

DIFICLIR 40 mg/ml granules for oral suspension may be used in adult patients with difficulties inswallowing tablets.

Extended-pulsed dosing

Fidaxomicin 200 mg tablets administered twice daily for days 1-5 (no intake of a tablet on day 6) thenonce daily on alternate days for days 7-25 (see section 5.1).

If a dose has been forgotten, the missed dose should be taken as soon as possible or, if it's nearly timefor the next dose, the tablet should be skipped altogether.

No dose adjustment is considered necessary (see section 5.2).

No dose adjustment is considered necessary. Due to the limited clinical data in this population,fidaxomicin should be used with caution in patients with severe renal impairment (see sections 4.4 and5.2).

No dose adjustment is considered necessary. Due to the limited clinical data in this population,fidaxomicin should be used with caution in patients with moderate to severe hepatic impairment (seesections 4.4 and 5.2).

The recommended dose in paediatric patients weighing at least 12.5 kg is 200 mg administered twicedaily (once every 12 hours) for 10 days using the film-coated tablets or the granules for oralsuspension.

Reduced doses are recommended for patients with a body weight of less than 12.5 kg. See the SmPCof DIFICLIR 40 mg/ml granules for oral suspension.

DIFICLIR is intended for oral use.

The film-coated tablets should be administered whole with water.

They can be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity reactions including severe angioedema have been reported (see section 4.8). If asevere allergic reaction occurs during treatment with fidaxomicin, the medicinal product should bediscontinued and appropriate measures taken.

Some patients with hypersensitivity reactions reported a history of allergy to macrolides. Fidaxomicinshould be used with caution in patients with a known macrolides allergy.

Due to limited clinical data, fidaxomicin should be used with caution in patients with severe renalimpairment or moderate to severe hepatic impairment (see section 5.2).

Pseudomembranous colitis, fulminant or life threatening CDI

Due to limited clinical data, fidaxomicin should be used with caution in patients withpseudomembranous colitis, fulminant or life threatening CDI.

Co-administration of potent P-glycoprotein inhibitors

Co-administration of potent P-glycoprotein inhibitors such as cyclosporine, ketoconazole,erythromycin, clarithromycin, verapamil, dronedarone and amiodarone is not recommended (seesections 4.5 and 5.2). In case fidaxomicin is administered concomitantly with potent P-glycoproteininhibitors, caution is advised.

Only one paediatric patient below 6 months of age has been exposed to fidaxomicin in clinical trials.

Therefore, patients below 6 months of age should be treated with caution.

Testing for C. difficile colonization or toxin is not recommended in children younger than 1 year dueto high rate of asymptomatic colonisation unless severe diarrhoea is present in infants with risk factorsfor stasis such as Hirschsprung disease, operated anal atresia or other severe motility disorders.

Alternative aetiologies should always be sought and C. difficile enterocolitis be proven.

Effect of P-gp inhibitors on fidaxomicin

Fidaxomicin is a substrate of P-gp. Co-administration of single doses of the P-gp inhibitorcyclosporine A and fidaxomicin in healthy volunteers, resulted in a 4- and 2-fold increase infidaxomicin Cmax and AUC, respectively and in a 9.5 and 4-fold increase in Cmax and AUC,respectively, of the main active metabolite OP-1118. As the clinical relevance of this increase inexposure is unclear, co-administration of potent inhibitors of P-gp, such as cyclosporine, ketoconazole,erythromycin, clarithromycin, verapamil, dronedarone and amiodarone is not recommended (seesections 4.4 and 5.2).

Effect of fidaxomicin on P-gp substrates

Fidaxomicin may be a mild to moderate inhibitor of intestinal P-gp.

Fidaxomicin (200 mg twice daily) had a small but not clinically relevant effect on digoxin exposure.

However, a larger effect on P-gp substrates with lower bioavailability more sensitive to intestinal P-gpinhibition such as dabigatran etexilat cannot be excluded.

Effect of fidaxomicin on other transporters

Fidaxomicin does not have a clinically significant effect on the exposure of rosuvastatin, a substratefor the transporters OATP2B1 and BCRP. Co-administration of 200 mg fidaxomicin twice daily witha single dose of 10 mg rosuvastatin to healthy subjects did not have a clinically significant effect onthe AUCinf of rosuvastatin.

Interaction studies have only been performed in adults.

There are no data available from the use of fidaxomicin in pregnant women. Animal studies did notindicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionarymeasure, it is preferable to avoid the use of fidaxomicin during pregnancy.

It is unknown whether fidaxomicin and its metabolites are excreted in human milk. Although noeffects on the breastfed newborns/infants are anticipated since the systemic exposure to fidaxomicin islow, a risk to the newborns/infants cannot be excluded. A decision must be made whether todiscontinue breast-feeding or to discontinue/abstain from fidaxomicin therapy, taking into account thebenefit of breast feeding for the child and the benefit of therapy for the woman.

Fidaxomicin had no effects on fertility when evaluated in rats (see section 5.3).

DIFICLIR has no or negligible influence on the ability to drive and use machines.

The most common adverse reactions are vomiting (1.2%), nausea (2.7%) and constipation (1.2%).

Table 1 displays adverse reactions associated with twice daily administration of fidaxomicin in thetreatment of C. difficile infection, reported in at least two patients, presented by system organ class.

The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to<1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), notknown (cannot be estimated from the available data). Within each frequency grouping, adversereactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions

MedDRA Common Uncommon Frequency not knownsystem organclass

Immune rash, hypersensitivity reactionssystem pruritus (angioedema, dyspnea)disorders

Metabolism decreased appetiteand nutritiondisorders

Nervous dizziness,system headache,disorders dysgeusia

Gastrointestinal vomiting, abdominal distention,disorders nausea, flatulence,constipation dry mouth

Acute hypersensitivity reactions, such as angioedema and dyspnea, have been reported duringpost-marketing (see section 4.3 and 4.4).

The safety and efficacy of fidaxomicin has been evaluated in 136 patients from birth to less than 18years of age. Frequency, type and severity of adverse reactions in children are expected to be the sameas in adults. In addition to the ADRs shown in table 1, two cases of urticaria were reported.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No adverse reactions for acute overdose have been reported during clinical studies or frompost-marketing data. However, the potential for adverse reactions cannot be ruled out and generalsupportive measures are recommended.

Pharmacotherapeutic group: Antidiarrheals, intestinal antiinflammatory/antiinfective agents,antibiotics, ATC code: A07AA12

Fidaxomicin is an antibiotic belonging to the macrocyclic class of antibacterials.

Fidaxomicin is bactericidal and inhibits RNA synthesis by bacterial RNA polymerase. It interfereswith RNA polymerase at a distinct site from that of rifamycins. Inhibition of the Clostridial RNApolymerase occurs at a concentration 20-fold lower than that for the E. coli enzyme (1 μM vs. 20 μM),partly explaining the significant specificity of fidaxomicin activity. Fidaxomicin has been shown toinhibit C. difficile sporulation in vitro.

Fidaxomicin is a locally acting drug. As a topical agent, systemic PK/PD relationships cannot beestablished, however in vitro data show fidaxomicin to have time-dependent bactericidal activity andsuggest time over MIC may be the parameter most predicative of clinical efficacy.

Fidaxomicin is a topically acting drug that cannot be used to treat systemic infections; therefore theestablishment of a clinical breakpoint is not relevant. The epidemiological cut-off value forfidaxomicin and C. difficile, distinguishing the wild-type population from isolates with acquiredresistance traits, is ≥1.0 mg/L.

Antimicrobial spectrum

Fidaxomicin is a narrow spectrum antimicrobial drug with bactericidal activity against C. difficile.

Fidaxomicin has an MIC90 of 0.25 mg/L versus C. difficile, and its main metabolite, OP-1118, has an

MIC90 of 8 mg/L. Gram negative organisms are intrinsically not susceptible to fidaxomicin.

Effect on the intestinal flora

Studies have demonstrated that fidaxomicin treatment did not affect Bacteroides concentrations orother major components of the microbiota in the faeces of CDI patients.

There are no known transferable elements that confer resistance to fidaxomicin. Also no cross-resistance has been discovered with any other antibiotic class including β-lactams, macrolides,metronidazole, quinolones, rifampin, and vancomycin. Specific mutations of RNA polymerase areassociated with reduced susceptibility to fidaxomicin.

The efficacy of fidaxomicin was evaluated in two pivotal, randomised, double-blind Phase 3 studies(Study 003 and 004). Fidaxomicin was compared with orally administered vancomycin. The primaryendpoint was clinical cure assessed after 12 days.

Non-inferiority of fidaxomicin compared with vancomycin was demonstrated in both studies (see

Table 2)

Table 2 Combined results of studies 003 and 004

Per Protocol (PP) Fidaxomicin Vancomycin 95% Confidence(200mg bid for 10 days) (125mg qid for 10 days) Interval*

Clinical Cure 91.9% 90.2%(442/481 patients) (467/518 patients) (-1.8, 5.3)modified Intent-to- Fidaxomicin Vancomycin 95% Confidence

Treat (mITT) (200mg bid) (125mg qid) Interval*

Clinical Cure 87.9% 86.2%(474/539 patients) (488/566 patients) (-2.3, 5.7)

*for treatment difference

The rate of recurrence in the 30 days following treatment was assessed as a secondary endpoint. Therate of recurrence (including relapses) was significantly lower with fidaxomicin (14.1% versus 26.0%with a 95% CI of [-16.8%, -6.8%]), however these trials were not prospectively designed to proveprevention of reinfection with a new strain.

Description of the patient population in the pivotal clinical trials in adults

In the two pivotal clinical trials of patients with CDI, 47.9% (479/999) of patients (per protocolpopulation) were ≥65 years of age and 27.5% (275/999) of patients were treated with concomitantantibiotics during the study period. Twenty-four percent of patients met at least one of the followingthree criteria at baseline for scoring severity: body temperature >38.5°C, leukocyte count >15,000, orcreatinine value ≥1.5 mg/dl. Patients with fulminant colitis and patients with multiple episodes(defined as more than one prior episode within the previous 3 months) of CDI were excluded from thestudies.

Trial with the extended-pulse fidaxomicin dosing (EXTEND)

EXTEND was a randomised, open-label study that compared extended-pulse fidaxomicin dosing withorally administered vancomycin. The primary endpoint was sustained clinical cure 30 days after endof treatment (Day 55 for fidaxomicin, day 40 for vancomycin). The sustained clinical cure 30 daysafter end of treatment was significantly higher for fidaxomicin vs. vancomycin (see Table 3).

Table 3 Results of EXTEND studymodified Intent-to- Fidaxomicin

Treat (200mg bid for 5 days Vancomycin 95% Confidence(mITT) then 200mg every other (125mg qid for 10 days) Interval*day)

Clinical cure 30 days 70.1% 59.2%after end of treatment (124/177 patients) (106/179 patients) (1.0, 20.7)

*for treatment difference

Description of the patient population in extended-pulse fidaxomicin dosing trial

The trial was conducted with adults aged 60 years and older. The median age of the patients was 75.72% (257/356) received other antibiotics within the last 90 days. 36.5% had a severe infection.

The safety and efficacy of fidaxomicin in paediatric patients from birth to less than 18 years of agewas investigated in a multicentre, investigator-blind, randomised, parallel group study where 148patients were randomised to either fidaxomicin or vancomycin in a 2:1 ratio. A total of 30, 49, 40 and29 patients were randomised in the age groups of birth to < 2 years, 2 to < 6 years, 6 to < 12 years and12 to < 18 years, respectively. Confirmed clinical response 2 days after end of treatment was similarbetween the fidaxomicin and vancomycin group (77.6% vs 70.5% with a point difference of 7.5% and95% CI for the difference of [-7.4%, 23.9%]). The rate of recurrence 30 days after end of treatmentwas numerically lower with fidaxomicin (11.8% vs 29.0%), but the rate difference is not statisticallysignificant (point difference of -15.8% and 95% CI for the difference of [-34.5%, 0.5%]). Bothtreatments had a similar safety profile.

The bioavailability in humans is unknown. In healthy adults, Cmax is approximately 9.88 ng/ml and

AUC0-t is 69.5 ng*hr/ml following administration of 200 mg fidaxomicin, with a Tmax of 1.75 hours. In

CDI patients, average peak plasma levels of fidaxomicin and its main metabolite OP-1118 tend to be2- to 6-fold higher than in healthy adults. There was very limited accumulation of fidaxomicin or

OP-1118 in plasma following administration of 200 mg fidaxomicin every 12 hours for 10 days.

Cmax for fidaxomicin and OP-1118 in plasma were 22% and 33% lower following a high fat meal vsfasting, but the extent of exposure (AUC0-t) was equivalent.

Fidaxomicin and the metabolite OP-1118 are substrates of P-gp.

In vitro studies showed that fidaxomicin and the metabolite OP-1118 are inhibitors of the transporters

BCRP, MRP2 and OATP2B1, but were not found to be substrates. Under conditions of clinical use,fidaxomicin has no clinically relevant effect on the exposure of rosuvastatin, a substrate for OATP2B1and BCRP (see section 4.5). The clinical relevance of MRP2 inhibition is not yet known.

The volume of distribution in humans is unknown, due to very limited absorption of fidaxomicin.

No extensive analysis of metabolites in plasma has been performed, due to low levels of systemicabsorption of fidaxomicin. A main metabolite, OP-1118, is formed through hydrolysis of theisobutyryl ester. In vitro metabolism studies showed that the formation of OP-1118 is not dependenton CYP450 enzymes. This metabolite also shows antimicrobial activity (see section 5.1).

Fidaxomicin does not induce or inhibit CYP450 enzymes in vitro.

Following a single dose of 200 mg fidaxomicin, the majority of the administered dose (over 92%) wasrecovered in the stool as fidaxomicin or its metabolite OP-1118 (66%). The main eliminationpathways of systemically available fidaxomicin have not been characterized. Elimination throughurine is negligible (<1%). Only very low levels of OP-1118 and no fidaxomicin was detectable inhuman urine. The half life of fidaxomicin is approximately 8-10 h.

Plasma levels appear to be elevated in the elderly (age ≥ 65 years). Fidaxomicin and OP-1118 levelswere approximately 2 times higher in patients ≥ 65 years compared to patients < 65 years. Thisdifference is not considered clinically relevant.

After administration of film-coated tablets, the mean (SD) plasma levels in the paediatric patients from6 to less than 18 years was 48.53 (69.85) ng/ml and 143.63 (286.31) ng/ml for fidaxomicin and itsmain metabolite OP-1118, respectively, at 1 to 5 hours postdose.

Data from an open label, single arm study in adult CDI patients with concomitant inflammatory boweldisease (IBD) indicated no major difference in plasma concentrations of fidaxomicin or its mainmetabolite OP-1118 in patients with IBD as compared with patients without IBD in other studies. Themaximum fidaxomicin and OP-1118 plasma levels in CDI patients with concomitant IBD were withinthe range of levels found in CDI patients without IBD.

Limited data from adult patients with an active history of chronic hepatic cirrhosis in the Phase 3studies showed that median plasma levels of fidaxomicin and OP-1118 may be approximately 2- and3-fold higher, respectively, than in non-cirrhotic patients.

Limited data from adult patients suggest that there is no major difference in plasma concentration offidaxomicin or OP-1118 between patients with reduced renal function (creatinine clearance< 50 ml/min) and patients with normal renal function (creatinine clearance ≥ 50 ml/min).

Gender, weight and race

Limited data suggest that gender, weight and race do not have any major influence on the plasmaconcentration of fidaxomicin or OP-1118.

Nonclinical data revealed no special hazard for humans based on conventional studies of safetypharmacology, repeat dose toxicity, genotoxicity, and reproductive toxicity.

Reproductive and fertility parameters showed no statistically significant differences in rats treated withfidaxomicin at doses up to 6.3 mg/kg/day (intravenous).

No target organs for toxicity were observed in juvenile animals, and no important potential risks havebeen observed in the nonclinical studies that might be relevant for paediatric patients.

Core tablets:

Microcrystalline cellulose

Pregelatinised starch (maize)

Hydroxypropyl cellulose

Butylated hydroxytoluene

Sodium starch glycolate

Magnesium stearate

Polyvinyl alcohol

Titanium dioxide (E171)

Talc

Polyethylene glycol

Lecithin (soy)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

100 x 1 film-coated tablet in alu/alu perforated unit dose blisters.20 x 1 film-coated tablet in alu/alu perforated unit dose blisters.

Not all pack sizes may be marketed.

Any unused product or waste material should be disposed of in accordance with local requirements.

Tillotts Pharma GmbH

Warmbacher Strasse 8079618 Rheinfelden

Germany

EU/1/11/733/003-004

Date of first authorisation: 5 December 2011

Date of latest renewal: 22 August 2016

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.